MHC class II antigen presentation in melanoma: impact on immune recognition

黑色素瘤中 MHC II 类抗原呈递：对免疫识别的影响

• 批准号: 10618790
• 负责人: KAREN TARASZKA HASTINGS
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618790
• 关键词: Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Area; Biological; CD8-Positive T-Lymphocytes; Cancer Patient; Combined Modality Therapy; Data; Development; Enzymes; Exhibits; Exposure to; Genomics; Goals; Health; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Immune; Immune mediated destruction; Immune system; Immunologics; Immunotherapy; Incidence; Knowledge; Laboratories; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Melanoma Cell; Military Personnel; Mutation; Neoplasm Metastasis; Occupational Exposure; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Research; Research Priority; Resistance; Risk Factors; Role; Specimen; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Training; Treatment Efficacy; Tumor Antigens; UV Radiation Exposure; Ultraviolet Rays; Veterans; active duty; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; antigen processing; cancer infiltrating T cells; cancer therapy; cancer type; cell type; clinically relevant; immune checkpoint blockade; immunogenic; immunoregulation; improved; in vivo; interest; melanoma; member; military service; military veteran; mouse model; neoplastic cell; novel; novel strategies; personalized medicine; precision medicine; protein complex; response; service member; side effect; therapy resistant; treatment response; tumor; tumor growth

Anti-tumor immune responses depend on T cell recognition of tumor antigens in the context of major histocompatibility complex (MHC) proteins to destroy tumors. While the MHC class I antigen presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors, the function of the MHC class II antigen presentation pathway in melanoma cells is not well understood. The goal of this proposal is to determine the function of MHC class II and the MHC class II antigen processing enzyme, GILT, in melanoma cells in regulating the anti-tumor immune response and response to immunotherapy. Preliminary results from the laboratory of the PI revealed that the MHC class II antigen presentation pathway and GILT, an enzyme involved in MHC class II antigen processing, are associated with improved survival in melanoma. Recent data from other groups show that induction of MHC class II expression on melanoma cells is associated with improved response to immune checkpoint blockade with anti-PD-1 in retrospective analyses. Immune checkpoint blockade with anti-PD-1 is being used to treat a rapidly growing number of cancer types and patients. Yet, the challenge remains that at least 60% and 25% of melanoma patients exhibit primary and acquired resistance to this therapy, respectively. The central hypothesis of this proposal is that the MHC class II antigen presentation pathway in melanoma cells enhances T cell-mediated destruction of tumors and improves the response to immune checkpoint blockade. To test this hypothesis clinically-relevant, immunogenic mouse models of melanoma will be employed to determine the role of GILT and MHC class II in melanoma cells on regulating the anti-tumor immune response and response to immunotherapy. This research team will determine the immunomodulatory effects of GILT and MHC class II expression in melanoma cells and identify immune cell types required for the modulation of tumor growth. Impact: New knowledge gained from the completion of these studies is anticipated to lead to improved patient outcomes. Determining the biological basis for MHC class II pathway members in the anti-tumor immune response and response to immunotherapy is expected to 1) identify novel causal determinants of immunologically hot vs. cold tumors, 2) provide support for a personalized medicine approach to optimize immunotherapy efficacy and limit side effects, and 3) define a novel pathway controlling anti-tumor immune responses that can be manipulated to augment treatment efficacy. The results of these studies are anticipated to be broadly applicable, as many cancers express MHC class II and all cancer types share the challenge of resistance to immunotherapy.

抗肿瘤的免疫反应取决于在主要背景下对肿瘤抗原的T细胞识别 组织相容性复合物（MHC）蛋白质破坏肿瘤。而MHC I类抗原呈现 黑色素瘤细胞中的途径在免疫介导的肿瘤破坏中具有公认的作用，该功能 黑素II类抗原表现途径的黑色素瘤细胞中尚不清楚。目标的目标 建议是确定MHC II类和MHC II类抗原加工酶的功能，镀金， 在调节抗肿瘤的免疫反应和对免疫疗法的反应中，黑色素瘤细胞中。初步的 PI实验室的结果表明，MHC II类抗原表现途径和镀金， 参与MHC II类抗原加工的酶与黑色素瘤中的生存率提高有关。 来自其他组的最新数据表明，MHC II类表达在黑色素瘤细胞上的诱导是 在回顾性分析中，与抗PD-1对免疫检查点阻断的反应有关。 使用抗PD-1的免疫检查点封锁正在用于治疗快速增长的癌症类型 和患者。然而，挑战仍然是，至少有60％和25％的黑色素瘤患者表现出初级和 分别获得了这种疗法的抵抗力。该提议的中心假设是MHC 黑色素瘤细胞中II类抗原表现途径增强了T细胞介导的肿瘤破坏和 改善对免疫检查点封锁的反应。为了检验该假设在临床上， 黑色素瘤的免疫原性小鼠模型将用于确定GILT和MHC II类在 黑色素瘤细胞调节抗肿瘤免疫反应和对免疫疗法的反应。这项研究 团队将确定黑色素瘤细胞中镀金和MHC II类表达的免疫调节作用 并确定调节肿瘤生长所需的免疫细胞类型。影响：新知识获得了 从完成这些研究后，预计将导致改善患者的结果。确定 抗肿瘤免疫反应中MHC II途径成员的生物学基础 预计免疫疗法1）鉴定免疫学热肿瘤的新型因果决定因素，2） 为一种个性化医学方法提供支持，以优化免疫疗法并限制一侧 效果和3）定义一种控制抗肿瘤免疫反应的新途径，可以操纵 增强治疗功效。这些研究的结果预计将是广泛适用的，因为许多 癌症表达MHC II类，所有癌症类型都面临着对免疫疗法的抗药性挑战。